This invention relates to (N-hydroxy)acylamino compounds and in particular to such compounds with a peptidic structure. This invention further relates to processes for preparing such compounds, to pharmaceutical and veterinary compositions containing them and to their use in methods of therapeutic treatment.
The compounds of this invention are inhibitors of one or more metalloproteinase enzymes. Metalloproteinases are a superfamily of proteinases (enzymes) whose numbers in recent years have increased dramatically. Based on structural and functional considerations these enzymes have been classified into families and subfamilies as described in N. M Hooper (1994) FEBS Letters 354:1-6. Examples of metalloproteinases include the matrix metalloproteinases (MMP) such as the collagenases (MMP1, MMP8, MMP13), the gelatinases (MMP2, MMP9), the stromelysins (MMP3, MMP10, MMP11), matrilysin (MMP7), metalloelastase (P12), enamelysin (MMP19), the MT-MMPs (MMP14, MMP15, MMP16, MMP17); the reprolysin or adamalysin or MDC family which includes the secretases and sheddases such as TNF converting enzymes (ADAM10 and TACE); the astacin family which include enzymes such as procollagen processing proteinase (PCP); and other metalloproteinases such as aggrecanase, the endothelin converting enzyme family and the angiotensin converting enzyme family.
Metalloproteinases are believed to be important in a plethora of physiological disease processes that involve tissue remodelling such as embryonic development, bone formation and uterine remodelling during menstruation. This is based on the ability of the metalloproteinases to cleave a broad range of matrix substrates such as collagen, proteoglycan and fibronectin. Metalloproteinases are also believed to be important in the processing, or secretion, of biological important cell mediators, such as tumour necrosis factor (TNF); and the post translational proteolysis processing, or shedding, of biologically important membrane proteins, such as the low affinity IgE receptor CD23 (for a more complete list see N. M. Hooper et al., (1997) Biochem J. 321:265-279).
Metalloproteinases have been associated with many disease conditions. Inhibition of the activity of one or more metalloproteinases may well be of benefit in these disease conditions, for example: various inflammatory and allergic diseases such as, inflammation of the joint (especially rheumatoid arthritis, osteoarthritis and gout), inflammation of the gastro-intestinal tract (especially inflammatory bowel disease, ulcerative colitis and gastritis), inflammation of the skin (especially psoriasis, eczema, dermatitis); in tumour metastasis or invasion; in disease associated with uncontrolled degradation of the extracellular matrix such as osteoarthritis; in bone resorptive disease (such as osteoporosis and Paget""s disease)); in diseases associated with aberrant angiogenesis; the enhanced collagen remodelling associated with diabetes, periodontal disease (such as gingivitis), corneal ulceration, ulceration of the skin, post-operative conditions (such as colonic anastomosis) and dermal wound healing; demyelinating diseases of the central and peripheral nervous systems (such as multiple sclerosis); Alzheimer""s disease; and extracellular matrix remodelling observed in cardiovascular diseases such as restenosis and atheroscelerosis.
A number of metalloproteinase inhibitors are known; different classes of compounds may have different degrees of potency and selectivity for inhibiting various metalloproteinases. We have discovered a new class of compounds that are inhibitors of metalloproteinases and are of particular interest in inhibiting MMP-13. The compounds of this invention have beneficial potency and/or pharmacokinetic properties.
MMP13, or collagenase 3, was initially cloned from a cDNA library derived from a breast tumour [J. M. P. Freije et al. (1994) Journal of Biological Chemistry 269(24: 16766-16773]. PCR-RNA analysis of RNAs from a wide range of tissues indicated that MMP13 expression was limited to breast carcinomas as it was not found in breast fibroadenomas, normal or resting mammary gland, placenta, liver, ovary, uterus, prostate or parotid gland or in breast cancer cell lines (T47-D, MCF-7 and ZR75-1). Subsequent to this observation MMP13 has been detected in transformed epidermal keratinocytes [N. Johansson et al., (1997) Cell Growth Differ. 8(2):243-250], squamous cell carcinomas [N. Johansson et al., (1997) Am. J. Pathol. 151(2):499-508] and epidermal tumours [K. Airola et al., (1997) J. Invest. Dermatol. 109(2):225-23 1]. These results are suggestive that MMP13 is secreted by transformed epithelial cells and may be involved in the extracellular matrix degradation and cell-matrix interaction associated with metastasis especially as observed in invasive breast cancer lesions and in malignant epithelia growth in skin carcinogenesis.
Recent published data implies that MMP13 plays a role in the turnover of other connective tissues. For instance, consistent with MMP13""s substrate specificity and preferential to degrade type II collagen [P. G. Mitchell et al., (1996) J. Clin Invest. 97(3):761-768; V. Knauper et al., (1996) The Biochemical Journal 271:1544-1550], MMP13 has been hypothesised to serve a role during primary ossification and skeletal remodelling [M. Stahle-Backdahl et al., (1997) Lab. Invest. 76(5):717-728; N. Johansson et al., (1997) Dev. Dyn. 208(3):387-397], in destructive joint diseases such as rheumatoid and osteo-arthritis [D. Wernicke et al., (1996) J. Rheumatol. 23:590-595; P. G. Mitchell et al., (1996) J. Clin. Invest. 97(3):761-768; O. Lindy et al., (1997) Arthritis Rheum 40(8):1391-1399]; and during the aseptic loosening of hip replacements [S. Imai et al., (1998) J. Bone Joint Surg. Br. 80(4):701-710]. MMP13 has also been implicated in chronic adult periodontitis as it has been localised to the epithelium of chronically inflamed mucosa human gingival tissue [V. J. Uitto et al., (1998) Am. J. Pathol 152(6):1489-1499] and in remodelling of the collagenous matrix in chronic wounds [M. Vaalamo et al., (1997) J. Invest. Dermatol. 109(1):96-101].
The present invention provides a compound of the formula (I):
R1xe2x80x94COxe2x80x94N(OH)xe2x80x94CR2R3xe2x80x94CR4R5xe2x80x94CONHxe2x80x94CR6R7xe2x80x94CONR8R9xe2x80x83xe2x80x83(I)
wherein:
R1 is C1-6alkyl, aryl or arylC1-6alkyl;
R2 is hydrogen, C1-6alkyl, C3-8,cycloalkyl, aryl or arylC1-6alkyl;
R3 is hydrogen, C1-6alkyl or arylC1-6alkyl;
or R2 and R3, together with the carbon atom to which they are joined, form a C3-8cycloalkyl ring;
R4 is hydrogen, C1-6alkyl or arylC1-6alkyl;
R5 is hydrogen, C1-6alkyl or arylC1-6alkyl;
R6 is hydrogen, C1-6alkyl, C2-6alkenyl, C3-8cycloalkylC1-6alkyl, arylC1-6alkyl, heteroarylC1-6alkyl or the side-chain of a naturally occurring amino acid;
R7 is hydrogen or C1-6alkyl;
R8 is hydrogen, C1-6alkyl, C3-8cycloalkyl, C3-8cycloalkenyl, arylC1-6alkyl, heteroarylC1-6alkyl or heterocyclylC1-6alkyl;
R9 is hydrogen or C1-6alkyl;
or R8 and R9, together with the nitrogen atom to which they are joined, form a heterocyclic ring;
wherein any group or ring in R1-R9 is optionally substituted;
or a pharmaceutically-acceptable salt or in vivo hydrolysable precursor thereof
xe2x80x9cAryl in the terms xe2x80x9carylxe2x80x9d and xe2x80x9carylC1-6alkylxe2x80x9d typically means phenyl or naphthyl, preferably phenyl. xe2x80x9cHeteroarylxe2x80x9d in the terms xe2x80x9cheteroarylxe2x80x9d and xe2x80x9cheteroarylC1-6alkylxe2x80x9d means an aromatic mono- or bicyclic 5-10 membered ring with up to five ring heteroatoms selected from nitrogen, oxygen and sulphur. Examples of xe2x80x98heteroarylxe2x80x99 include thienyl, pyrrolyl, furanyl, imidazolyl, thiazolyl, pyrimidinyl, pyridinyl, indolyl, benzimidazolyl, benzthiazolyl, quinolinyl and isoquinolinyl. xe2x80x9cHeterocyclylxe2x80x9d in the terms xe2x80x9cheterocyclylxe2x80x9d and heterocyclylC1-6alkylxe2x80x9d means a non-aromatic mono- or bicyclic 5-10 membered ring with up to five ring hetero atoms selected from nitrogen, oxygen and sulphur. Examples of xe2x80x98heterocyclylxe2x80x99 include pyrrolidinyl, morpholinyl, piperidinyl, dihydropyridinyl and dihydropyrimidinyl.
Any group or ring in R1-R9 may be optionally substituted, for example by up to three substituents which may be the same or different. Typical substituents include: hydroxy, C1-6alkoxy for example methoxy, mercapto, C1-6alkylthio for example methylthio, amino, C1-6alalkylamino for example methylamino, di-(C1-6alkyl)amino for example dimethylamino, carboxy, carbamoyl, C1-6alkylcarbamoyl for example methylcarbamoyl, di-C1-6alkylcarbamoyl for example dimethylcarbamoyl, C1-6alkylsulphonyl for example methylsulphonyl, arylsulphonyl for example phenylsulphonyl, C1-6alkylaminosulphonyl for example methylaminosulphonyl, di-(C1-6alkyl)aminosulphonyl for example dimethylamino-sulphonyl, nitro, cyano, cyanoC1-6alkyl for example cyanomethyl, hydroxyC1-6alkyl for example hydroxymethyl, aminoC1-6alkyl for example aminoethyl, C1-6alkanoylamino for example acetamido, C1-6alkoxycarbonylamino for example methoxycarbonylamino, C1-6alkanoyl for example acetyl, C1-6alkanoyloxy for example acetoxy, C1-6alalkyl for example methyl, ethyl, isopropyl or tert-butyl, halo for example fluoro, chloro or bromo, trifluoromethyl, aryl for example phenyl, arylC1-6alkyl for example benzyl, aryloxy for example phenoxy, arylC1-6alkoxy for example benzyloxy, heteroaryl, heteroarylC1-6alkyl, heterocyclyl and heterocyclylC1-6alkyl. The term xe2x80x9cside chain of a naturally occurring amino acidxe2x80x9d means the side chain X of an amino acid NH2xe2x80x94CHXxe2x80x94COOH. Suitable amino acids include alanine, arginine, aspartic acid, cysteine, asparagine, glutamine, histidine, homoserine, isoleucine, leucine, lysine, methionine, norleucine, norvaline, ornithine, serine, threonine, tryptophan, tyrosine and valine.
The compounds of the present invention possess a number of chiral centres (dependent on the nature of the variable), for example at xe2x80x94CR2R3xe2x80x94, at xe2x80x94CR4R5xe2x80x94, at xe2x80x94CR6R7xe2x80x94 and possibly in the variables R1-R9. The present invention covers all isomers, diastereoisomers, etc. and mixtures thereof that inhibit one or more metalloproteinase enzymes.
Particular groups for R1 include C1-6alkyl for example methyl, ethyl, isopropyl, n-propyl, isobutyl, sec-butyl, n-butyl, tert-butyl, isopentyl, n-pentyl or hexyl; C1-6alkyl interrupted by an oxygen or sulphur atom for example methoxymethyl, methoxyethyl, ethoxyethyl, methoxyethyl, methoxypropyl, ethoxyethyl, propoxymethyl, ethylthioethyl or methylthiopropyl; phenylC1-6alkyl for example benzyl, phenethyl, phenylpropyl or phenylbutyl; phenylC1-6alkyl interrupted by oxygen or sulphur for example benzyloxybutyl or benzyloxypropyl; and aryl for example phenyl or trifluoromethylphenyl.
Preferably R1 is methyl, ethyl, isopropyl, tert-butyl, isobutyl, benzyl, phenethyl or phenyl.
Particular groups for R2 include hydrogen, C1-6alkyl for example methyl or ethyl; C3-8cycloalkyl for example cyclobutyl, cyclopentyl or cyclohexyl; aryl for example phenyl; and arylC1-6alkyl for example benzyl, phenethyl or phenylpropyl.
Preferably R2 is hydrogen or methyl.
Particular groups for R3 include hydrogen; C1-6alkyl for example methyl or ethyl; and arylC1-6alkyl for example benzyl or phenethyl.
Preferably R3 is hydrogen.
Particular groups for R4 include hydrogen; C1-6alkyl for example methyl, ethyl, isopropyl, n-propyl, isobutyl, sec-butyl, n-butyl, tert-butyl, isopentyl, n-pentyl or hexyl; C1-6alkyl interrupted by an oxygen or sulphur atom for example methoxymethyl, methoxyethyl, ethoxyethyl, methoxyethyl, methoxypropyl, ethoxyethyl, propoxymethyl, ethylthioethyl or methylthiopropyl; phenylC1-6alkyl for example benzyl, phenethyl, phenylpropyl or phenylbutyl; halophenylC1-6alkyl for example fluorophenethyl, fluorophenylpropyl, fluorophenylbutyl or chlorophenylbutyl; and phenylC1-6alkyl interrupted by oxygen or sulphur for example benzyloxybutyl or benzyloxypropyl.
Preferably R4 is benzyl, phenethyl, phenylpropyl, phenylbutyl or fluorophenylbutyl.
Particular groups for R5 include hydrogen; C1-6alkyl for example methyl or ethyl; and phenylC1-6alkyl for example benzyl.
Preferably R5 is hydrogen or methyl.
There is a chiral centre at xe2x80x94CR4R5xe2x80x94 (when R4 and R5 are not the same); it is preferred that this centre has the configuration indicated in formula (II) hereinafter. For example, for most values of R4 (when R5 is hydrogen), this centre will have the R stereochemistry under the Cahn-Prelog-Ingold sequence rules.
Particular groups for R6 include C1-6alkyl for example methyl, ethyl, isopropyl, n-propyl, n-butyl, isobutyl, sec-butyl, tert-butyl, isopentyl, n-pentyl or hexyl; C1-6alkyl interrupted by an oxygen or sulphur atom for example methoxyethyl, methoxypropyl, methylthioethyl or 1,1-dimethylmethylthiomethyl (MeSCMe2xe2x80x94); C3-8cycloalkylC1-6alkyl for example cyclopentylmethyl, cyclohexylmethyl or cycloheptylmethyl; or phenylC1-6alkyl for example benzyl or phenethyl.
Preferably R6 is isobutyl, tert-butyl, 1,1-dimethylmethylthiomethyl, cyclopentylmethyl, cyclohexylmethyl or benzyl with tert-butyl being most preferred.
Particular groups for R7 include hydrogen or C1-6alkyl for example methyl or ethyl.
Preferably R7 is hydrogen.
There is a chiral centre at xe2x80x94CR6R7xe2x80x94 (when R6 and R7 are not the same); it is preferred that this centre has the configuration indicated in formula (II) hereinafter. For example, for most values of R6 (when R7 is hydrogen) this centre will have the S-stereochemistry.
Particular groups for R8 include C1-6alkyl for example methyl, ethyl, n-propyl, isopropyl, tert-butyl or n-butyl; C1-6alkyl interrupted by an oxygen or sulphur atom for example hydroxyethyl, methoxyethyl, methylthioethyl or ethoxyethyl; C2-6alkyl substituted by either amino, C1-6alkylamino or di-C1-6alkylamino; phenylC1-6alkyl for example benzyl, phenethyl or phenylpropyl; heterocyclicalkyl for example 2-morpholinoethyl, 2-piperazinoethyl, 2-(N-methylpiperazino)ethyl or 2-piperidinoethyl; or C3-8cycloalkylC1-6alkyl for example cyclopropylmethyl cyclobutylmethyl or cyclopentylmethyl.
Preferably R8 is methyl, ethyl, n-propyl, isobutyl tert-butyl, benzyl or phenethyl. Of these methyl is most preferred.
Particular groups for R9 are hydrogen and C1-6alkyl for example methyl or ethyl. Preferably R9 is hydrogen.
A particularly suitable class of compounds of the present invention is that of formula (II): 
wherein R1-R9 are as hereinbefore defined.
A preferred class of compounds of the formula (II) is that wherein R1 is methyl, ethyl, isopropyl, benzyl, phenethyl or phenyl, R2, R3, R5 and R7 are all hydrogen; R4 is benzyl, phenethyl, phenylpropyl, phenylbutyl or 4-fluorophenylbutyl; R6 is isobutyl, tert-butyl, 1,1-dimethylmethylthiomethyl, cyclopentylmethyl, cyclohexylmethyl or benzyl; R8 is methyl, ethyl, n-propyl, isobutyl, tert-butyl, 2-dimethylaminoethyl, benzyl or phenethyl, and R4 is hydrogen or methyl.
Particular compounds of this invention include those of the examples hereinbelow and those of the formula (II) wherein R1 is phenyl or tert-butyl; R4 is phenylpropyl; R6 is tert-butyl; R8 is methyl and R2, R3, R5 and R7 are each hydrogen.
Suitable pharmaceutically acceptable salts include acid addition salts such as hydrochloride, hydrobromide, citrate and maleate salts and salts formed with phosphoric and sulphuric acid. In another aspect suitable salts are base salts such as an alkali metal salt for example sodium or potassium, an alkaline earth metal salt for example calcium or magnesium, or organic amine salt for example triethylamine.
In vivo hydrolysable precursors are those pharmaceutically acceptable precursors that hydrolyse in the human body to produce the parent compound. Such precursors can be identified by administering, for example intravenously to a test animal, the compound under test and subsequently examining the test animal""s body fluids. Suitable in vivo hydrolysable precursors include esters, suitable examples of which for carboxy include methoxymethyl and for hydroxy include acetyl.
In order to use a compound of the formula (I) or a pharmaceutically acceptable salt or in vivo hydrolysable precursor thereof for the therapeutic treatment (including prophylactic treatment) of mammals including humans, it is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.
Therefore in another aspect the present invention provides a pharmaceutical composition which comprises a compound of the formula (I) or a pharmaceutically acceptable salt or an in vivo hydrolysable precursor and pharmaceutically acceptable carrier.
The pharmaceutical compositions of this invention may be administered in standard manner for the disease condition that it is desired to treat, for example by oral, topical, parenteral, buccal, nasal, vaginal or rectal administration or by inhalation. For these purposes the compounds of this invention may be formulated by means known in the art into the form of, for example, tablets, capsules, aqueous or oily solutions, suspensions, emulsions, creams, ointments, gels, nasal sprays, suppositories, finely divided powders or aerosols for inhalation, and for parenteral use (including intravenous, intramuscular or infusion) sterile aqueous or oily solutions or suspensions or sterile emulsions.
In addition to the compounds of the present invention the pharmaceutical composition of this invention may also contain, or be co-administered (simultaneously or sequentially) with, one or more pharmacological agents of value in treating one or more disease conditions referred to hereinabove.
The pharmaceutical compositions of this invention will normally be administered to humans so that, for example, a daily dose of 0.5 to 75 mg/kg body weight (and preferably of 0.5 to 30 mg/kg body weight) is received. This daily dose may be given in divided doses as necessary, the precise amount of the compound received and the route of administration depending on the weight, age and sex of the patient being treated and on the particular disease condition being treated according to principles known in the art.
Typically unit dosage forms will contain about 1 mg to 500 mg of a compound of this invention.
Therefore in a further aspect, the present invention provides a compound of the formula (I) or a pharmaceutically acceptable salt or in vivo hydrolysable precursor thereof for use in a method of therapeutic treatment of the human or animal body.
In yet a further aspect the present invention provides a method of treating a disease condition mediated by one or more metalloproteinase enzymes which comprises administering to a warm-blooded animal an effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt or in vivo hydrolysable precursor thereof. The present invention also provides the use of a compound of the formula (I) or a pharmaceutically acceptable salt or in vivo hydrolysable precursor thereof in the preparation of a medicament for use in a disease condition mediated by one or more metalloproteinase enzymes.
In another aspect the present invention provides a process for preparing a compound of the formula (I) or a pharmaceutically acceptable salt or in vivo hydrolysable precursor thereof which process comprises deprotecting a compound of the formula (III):
R1xe2x80x94COxe2x80x94N(OP)xe2x80x94CR2R3xe2x80x94CR4R5xe2x80x94CONHxe2x80x94CR6R7xe2x80x94CONR8R9xe2x80x83xe2x80x83(III)
wherein R1-R9 as defined hereinbefore and P is a protecting group:
wherein any other functional group is protected, if necessary, and:
i) removing any other protecting groups;
ii) optionally forming a pharmaceutically acceptable salt or in vivo hydrolysable precursor.
P is any suitable protecting group known for protecting the O-atom of a hydroxylamine group. Typically P is benzyl, substituted benzyl such as p-methoxybenzyl, tert-butyl or silyl. Such groups may be removed under standard conditions known in the art; for example a benzyl protecting group may be removed by catalytic hydrogenation.
Protecting groups may in general be chosen from any of the groups described in the literature or known to the skilled chemist as appropriate for the protection of the group in question, and may be introduced by conventional methods; see for example Protecting Groups in Organic Chemistry; Theodora W. Greene.
Protecting groups for other functional groups may be removed by any convenient method as described in the literature or known to the skilled chemist as appropriate for the removal of the protecting group in question, such methods being chosen so as to effect removal of the protecting group with minimum disturbance of groups elsewhere in the molecule.
Specific examples of protecting groups are given below for the salke of convenience. It will be understood that these examples are not exhaustive. Where specific examples of methods for the removal of protecting groups are given below these are similarly not exhaustive. The use of protecting groups and methods of deprotection not specifically mentioned is of course within the scope of the invention.
A carboxyl protecting group may be the residue of an ester-forming aliphatic or araliphatic alcohol or of an ester-forming silanol (the said alcohol or silanol preferably containing C1-20carbon atoms).
Examples of carboxy protecting groups include straight or branched chain C1-12alkyl groups (eg isopropyl, t-butyl); C1-4alkoxyC1-4alkyl groups (eg methoxymethyl, ethoxymethyl, isobutoxymethyl); C1-4acyloxyC1-4alkyl groups, (eg acetoxymethyl, propionyloxymethyl, butyryloxymethyl, pivaloyloxymethyl), C1-4alkoxycarbonyloxy C1-4alkyl groups (eg 1-methoxycarbonyloxyethyl, 1-ethoxycarbonyloxyethyl); aryl C1-4alkyl groups (eg benzyl, p-methoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, benzhydryl and phthalidyl); tri(C1-4alkyl)silyl groups (eg trimethylsilyl and t-butyldimethylsilyl); tri(C1-4alkyl)silyl lower alkyl groups (eg trimethylsilylethyl); and C2-6alkenyl groups (eg allyl and vinylethyl).
Methods particularly appropriate for the removal of carboxyl protecting groups include for example acid-, base-, metal- or enzymically-catalysed hydrolysis.
Examples of hydroxyl protecting groups include C1-4alkyl groups (eg t-butyl), C2-4alkenyl groups (eg allyl); C1-4alkanoyl groups (eg acetyl); C1-4alkoxycarbonyl groups (eg t-butoxycarbonyl); C2-4alkenyloxycarbonyl groups (eg allyloxycarbonyl); arylC1-4alkoxycarbonyl groups (eg benzoyloxycarbonyl, p-methoxybenzyloxycarbonyl, o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl); tri-C1-4alkylsilyl (eg trimethylsilyl, t-butyldimethylsilyl) and arylC1-4alkyl (eg benzyl) groups.
Examples of amino protecting groups include formyl, aralkyl groups (eg benzyl and substituted benzyl, p-methoxybenzyl, nitrobenzyl and 2,4-dimethoxybenzyl, and triphenylmethyl); di-p-anisylmethyl and furylmethyl groups; C1-4alkoxycarbonyl (eg t-butoxycarbonyl); C2-4alkenyloxycarbonyl (eg allyloxycarbonyl); aryl C1-4alkoxycarbonyl groups (eg benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl); triC1-4alkylsilyl (eg trimethylsilyl and t-butyldimethylsilyl); alkylidene (eg methylidene); benzylidene and substituted benzyldene groups.
Methods appropriate for removal of hydroxy and amino protecting groups include, for example, acid-, base-, metal- or enzymically-catalysed hydrolysis, for groups such as p-nitrobenzyloxycarbonyl, hydrogenation and for groups such as o-nitrobenzyloxycarbonyl, photolytically.
The compounds of the formula (III) may be prepared by:
a) reacting a compound of the formula (IV) with a compound of the formula (V):
R1xe2x80x94COxe2x80x94N(OP)xe2x80x94CR2R3xe2x80x94CR4R5xe2x80x94COOHxe2x80x83xe2x80x83(IV)
NH2xe2x80x94CR6R7xe2x80x94CONR8R9xe2x80x83xe2x80x83(V)
xe2x80x83wherein R1-R9 and P are as hereinbefore defined, under standard peptide coupling conditions;
b) reacting a compound of the formula (VI) with a compound of the formula (VII):
R1xe2x80x94COxe2x80x94N(OP)xe2x80x94CR2R3xe2x80x94CR4R5xe2x80x94CONHxe2x80x94CR6R7xe2x80x94COOHxe2x80x83xe2x80x83(VI)
HNR8R9xe2x80x83xe2x80x83(VII)
xe2x80x83wherein R1-R9 and P are as hereinbefore defined, under standard peptide coupling conditions;
c) acylating a compound of the formula (VIII) with an acylating agent R1xe2x80x94COxe2x80x94X:
P1Oxe2x80x94HNxe2x80x94CR2R3xe2x80x94CR4R5xe2x80x94CONHxe2x80x94CR6R7xe2x80x94CONR8R9xe2x80x83xe2x80x83(VIII)
xe2x80x83wherein R1-R9 are as hereinbefore defined and P1 is hydrogen or a group P as hereinbefore defined.
Standard peptide coupling conditions are described in many articles and textbooks.
The compounds of the formula (V) may be prepared by reacting a compound of the formula (VII) with a compound of the formula (IX) under standard peptide coupling conditions:
NH2CR6R7COOHxe2x80x83xe2x80x83(IX)
wherein R6 and R7 are as hereinbefore defined.
The compounds of the formula (IV) may be prepared by standard methods of organic synthesis, for example see the methods of the Examples hereinbelow.
The compounds of the formula (VI) may be prepared by reacting a compound of the formula (IV) with a compound of the formula (IX) under standard peptide coupling conditions.
The compounds of the formula (VIII) are acylated to form the compounds of the formula (III). When P1 is hydrogen, acylation may result in acylation on both the nitrogen and oxygen atoms of the hydroxylamine function. If this is the case, the O-acyl group may be removed under standard deprotection conditions.
Suitable acylating agents include acetyl chloride, acetic anhydride and related compounds.
The compounds of the formula (VIII) are prepared by methods similar to those described hereinabove for preparing the compounds of the formula (III).